ABSTRACT Project 3 (Kirk Erickson, PL) Exercise effects on neural circuits for CVD risk The mechanisms by which physical activity (PA) may reduce CVD risk remain unclear. Multiple lines of evidence, however, show that PA ? particularly aerobic exercise ? exerts beneficial effects on brain health and brain plasticity. Critically, the brain areas reliably affected by exercise are visceral control areas under study in Projects (Ps) 1 and 2. These areas regulate aspects of peripheral autonomic, neuroendocrine, and immune physiology that are involved in conferring CVD risk and favorably affected by exercise. Accordingly, we propose to integrate historically separate lines of work on (1) exercise and CVD risk, (2) exercise and brain plasticity, and (3) exercise and stress, affect, and physiological control. To this end, we propose a 12-month intervention in which 150 midlife and inactive adults will be randomized to (1) 150 min/wk of moderate exercise (e.g., brisk walking; N=75) or (2) a light stretching control group with similar health instruction and social interaction as the treatment group (N=75). We will collect neuroimaging measures integral to Ps 1-2: behaviorally-evoked neural activity, cerebral perfusion and functional connectivity, white matter integrity, and gray matter morphology at 3 waves (baseline, 6-months, 12-months). Moreover, we use ambulatory CV monitoring and ecological momentary assessment (EMA) methods for the first time to test whether exercise impacts daily life stress physiology and affect, and whether these effects are partly explained by changes to visceral control areas. Our design allows us to test several hypotheses by the following Aims: Aim 1: To determine the neurobiology of exercise and biological CVD risk factors: (1A) Body-to-Brain hypothesis: Exercise-induced changes in peripheral markers of CVD risk (e.g., insulin resistance, cardiorespiratory fitness, peripheral vascular function) will precede and partly explain (statistically mediate) some of the exercise-induced changes in functional and structural features of areas defining visceral control circuits. (1B) Brain-to-Body hypothesis: Exercise-induced changes in functional and structural features of areas defining visceral control circuits precede and partly explain (statistically mediate) consequent changes in autonomic and neuroendocrine mediators of CVD risk that are under neural regulation, including baroreflex sensitivity, heart rate variability, and glucocorticoid control. Aim 2: To determine the neurobiology of exercise and stress- and affect-related CVD risk factors: (2A) Stress-related parameters of CVD risk: Exercise will induce changes in visceral control areas engaged by an fMRI stress battery, and these changes will partly explain exercise-induced reductions in cardiovascular stress reactivity in daily life (synergy with P's 1 & 2). (2B) Affect-related parameters of CVD risk: Exercise will induce changes in visceral control areas engaged by an fMRI emotion processing and regulation paradigm in synergy with P1, and these changes will partly explain exercise-induced improvements in affect measured in daily life by EMA and by conventional self-report instruments in synergy with P2. The public health significance of this Project is that it is designed to more precisely define and refine neurobiological targets to reduce CVD risk.